School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
Department of Oncology, Affiliated Hongqi Hospital of Mudanjiang Medical College, Mudanjiang 157011, P. R. China.
ACS Appl Mater Interfaces. 2022 May 11;14(18):20762-20777. doi: 10.1021/acsami.2c03523. Epub 2022 Apr 27.
The tumor immunosuppressive microenvironment (TIM) greatly hindered the efficacy of cancer immunotherapy. Overexpressed indoleamine 2,3-dioxygenase-1 (IDO1) in tumor tissues plays a vital role in TIM generation, and downregulation of IDO1 expression may reverse TIM. Inspired by the Watson-Crick base-pairing rule, a versatile noncationic miRNA vector (miDAC@PDA) is developed for cancer immunotherapy. Doxorubicin (DOX), adenosine triphosphate (ATP), and copper ions (Cu) are coassembled into coordination polymer nanoparticles (DAC) and bind miRNA the hydrogen bond interaction (miDAC) between adenine residues (ATP) and uracil residues (miRNA). Polydopamine (PDA) is deposited onto the surface of miDAC for photothermal therapy. miDAC@PDA can efficiently accumulate into tumor tissues for cellular uptake. Under laser irradiation and high intracellular GSH levels, the PDA shell of miDAC@PDA can dissociate from miDAC for miRNA release due to local hyperthermia. Cu-mediated GSH consumption and intracellular ATP release can amplify the DOX-based immunogenic cell death (ICD) cascade, together with miR-448-mediated IDO1 inhibition, and these versatile nanoplexes will not only restrain primary tumor growth but also display a remarkable abscopal effect on distant tumors. Collectively, our study provides a unique strategy for intracellular gene delivery and an inspirational approach for multimechanism cancer management.
肿瘤免疫抑制微环境（TIM）极大地阻碍了癌症免疫疗法的疗效。肿瘤组织中过表达的吲哚胺 2,3-双加氧酶-1（IDO1）在 TIM 的产生中起着至关重要的作用，下调 IDO1 的表达可能会逆转 TIM。受沃森-克里克碱基配对规则的启发，开发了一种多功能非阳离子 miRNA 载体（miDAC@PDA）用于癌症免疫治疗。阿霉素（DOX）、三磷酸腺苷（ATP）和铜离子（Cu）共组装成配位聚合物纳米颗粒（DAC），并通过氢键相互作用（miDAC）结合 miRNA 中的腺嘌呤残基（ATP）和尿嘧啶残基（miRNA）。聚多巴胺（PDA）沉积在 miDAC 的表面用于光热治疗。miDAC@PDA 可以有效地聚集到肿瘤组织中进行细胞摄取。在激光照射和高细胞内 GSH 水平下，miDAC@PDA 的 PDA 壳由于局部过热而从 miDAC 上解离以释放 miRNA。Cu 介导的 GSH 消耗和细胞内 ATP 释放可以放大基于 DOX 的免疫原性细胞死亡（ICD）级联反应，同时 miR-448 介导的 IDO1 抑制，这些多功能纳米复合物不仅可以抑制原发性肿瘤生长，而且对远处的肿瘤也表现出显著的远隔效应。总之，我们的研究为细胞内基因传递提供了一种独特的策略，并为多机制癌症管理提供了一种有启发性的方法。
